Edgar Schaeffer

Plant compounds that inhibit snake venom activities are relevant and can provide active molecules to counteract snake venom effects. Numerous studies on snake viperid venoms found that metalloproteinases play a significant role in the pathophysiology of hemorrhage that occurs on envenomation. Preclinical studies using vitro and in vivo protocols investigated natural compounds and viperid snake venoms, evaluating the enzymatic, procoagulant, hemorrhagic, edematogenic, myotoxic, and lethal activities. Many studies focused on Bothrops venoms and ascribed that angiorrhexis and hemorrhage resulted from the metalloproteinase action on collagen in the basal lamina. This effect resulted in a combined action with phospholipase A2 and hyaluronidase, inducing hemorrhage, edema, and necrosis. Due to the lack of efficient antivenoms in remote areas, traditional native plant treatments remain common, especially in the Amazon. Our group studied plant extracts, isolated compounds, and lapachol synthetic derivative analogs with selective inhibition for Bothrops venom proteolytic and hemorrhagic activity and devoid of phospholipase activity. We highlight those new synthetic naphthoquinones which inhibit snake venom metalloproteinases and that are devoid of other venom enzyme inhibition. This review shows the potential use of snake venom effects, mainly Bothrops venom metalloproteinase activity, as a tool to identify and develop new active molecules against hemorrhagic effects.

Leishmaniasis remains a significant public health problem in Brazil, particularly due to Leishmania (Viannia) braziliensis, which is associated with severe dermatological syndromes. The current treatments are limited by toxicity and uncertain efficacy, highlighting the need for new compounds with pharmacological potential. This study investigates chalcones as multitarget binding agents for oligopeptidase B (OPB) and cysteine proteinase B (CPB), which are critical pathogenic determinants of L. (V.) braziliensis. The methodology involved replacing methoxy groups with aryl motifs at various positions within the chalcone structures and introducing specific functional groups at the C-4 position. This was followed by a virtual screening approach using molecular docking to assess interactions with the target proteinases. Several chalcones from the virtual library (n = 178) exhibited high binding affinities for OPB and CPB, outperforming control ligands. A total of 30 chalcones with multitarget potential were identified, with fluorinated compounds C-191 and C-135 emerging as promising inhibitors, distinguished by the best energy rankings for both enzymes. ADMET analyses confirmed the viability of these chalcones as drug candidates, with most adhering to Lipinski’s rules. These data suggest that chalcones may provide new multitarget treatment options for leishmaniasis.

Endemic and pandemic viruses represent significant public health challenges, leading to substantial morbidity and mortality over time. The COVID-19 pandemic has underscored the urgent need for the development and discovery of new, potent antiviral agents. In this study, we present the synthesis and anti-SARS-CoV-2 activity of a series of benzocarbazoledinones, assessed using cell-based screening assays. Our results indicate that four compounds (4a, 4b, 4d, and 4i) exhibit EC50 values below 4 μM without cytotoxic effects in Calu-3 cells. Mechanistic investigations focused on the inhibition of the SARS-CoV-2 main protease (Mpro) and papain-like protease (PLpro) have used enzymatic assays. Notably, compounds 4a and 4b showed Mpro inhibition activity with IC50 values of 0.11 ± 0.05 and 0.37 ± 0.05 µM, respectively. Furthermore, in silico molecular docking, physicochemical, and pharmacokinetic studies were conducted to validate the mechanism and assess bioavailability. Compound 4a was selected for preliminary drug-likeness analysis and in vivo pharmacokinetics investigations, which yielded promising results and corroborated the in vitro and in silico findings, reinforcing its potential as an anti-SARS-CoV-2 lead compound.